Minimum effective dose of chenic acid for gallstone patients: reduction with bedtime administration and

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1 Gut, 1982, 23, Minimum effetive dose of heni id for gllstone ptients: redution with bedtime dministrtion nd low holesterol diet D P MUDGL, R M KUPFER, ND T C NORTHFIELD* From the Normn Tnner Gstroenterology Unit, St. Jmes's Hospitl nd Deprtment of Mediine, St. George's Hospitl Medil Shool, London SUMMRY The im of this study ws to determine whether bedtime dministrtion nd low holesterol diet redue the minimum effetive dose of henodeoxyholi (heni) id, defined s the dose giving men holesterol sturtion index of.8. Dose response studies were rried out in 1 ptients with rdioluent gllstones in funtioning gllbldder during three different tretment regimens. On eh regimen, ll ptients reeived three different doses of henodeoxyholi id in rndom order for one month eh. Bedtime heni id plus low holesterol diet gve the gretest redution in sturtion index. signifint dose/response reltionship ws found on eh regimen. On the onventionl regimen of meltime heni id, the minimum effetive dose ws 14 mg/kg/dy; on bedtime heni id it ws 12-4 mg/kg/dy; nd on bedtime heni id plus low holesterol diet it ws further redued to 8-4 mg/kg/dy (P<.1). There ws dose-relted inrese in bowel frequeny, whih ws bsent t 1.6 mg/kg/dy nd below. We onlude tht dministrtion of heni id t bedtime with low holesterol diet enbles the minimum effetive dose for gllstone dissolution to be pproximtely hlved, thus preventing dirrhoe nd reduing the ost of tretment. Orl dministrtion of henodeoxyholi (heni) id to holesterol gllstone ptients redues holesterol sturtion index of fsting gllbldder bile nd indues gllstone dissolution. 1-4 men sturtion index of 8 is ssoited with onsistent dissolution of rdioluent gllstones.5 When heni id is tken in the onventionl mnner t meltimes, redution in men sturtion index to.8 hs been reported with the urrently reommended dose of mg/kg/dy.5 With the lterntive bile id, ursodeoxyholi id, n equl effet hs been hieved with the lower dose of 9 7 mg/kg/dy.6 We hve previously shown tht the effet of heni id (15 mg/kg/dy) on sturtion index of fsting gllbldder bile is enhned by bedtime dministrtion7 nd by low holesterol diet.8 The im of the present study ws to ssess the effet of these two therpeuti mesures on the minimum effetive dose of heni id, defined s the dose giving men *ddress for reprint requests: Dr T C Northfield, Deprtment of Mediine, St. George's Hospitl Medil Shool, Crnmer Terre, London SW17 ORE, Englnd. Reeived for publition 1 September 1981 sturtion index of -8, in different group of ptients to tht previously reported.7'8 redution in minimum effetive dose would be expeted to redue dose-relted dirrhoe,t 3 4 9s well s the ost of tretment. We hve therefore rried out dose response studies in 1 gllstone ptients on three seprte tretment regimens (meltime heni id, bedtime heni id, nd bedtime heni id plus low holesterol diet). Methods PTI E NTS Ten ptients (four men nd six women) with rdioluent gllstones in gllbldders tht opified during orl holeystogrm were studied. ll ptients hd norml liver funtion tests (bilirubin, SGOT, SGPT, lkline phosphtse, nd serum lbumin). Detils of ptients re given in the Tble. Perentge idel body weight ws 16-7±3- (men±sem) in the 1 ptients prtiipting in regimens nd B nd in the six ptients prtiipting in regimen C it ws 14.2±3 9%. Throughout the 28 Gut: first published s /gut on 1 pril Downloded from on 2 ugust 218 by guest. Proteted by opyright.

2 Minimum effetive dose ofheni idfor gllstoneptients Tble Detils of individul ptients Sex ge Wt % Initil Tretment (yr) (kg) IBW SI regimen order F BC M BC F BC M BC F BC M BC M B F B F B F B Men IBW: idel body weight. SI: sturtion index. study period, the mximum hnge in weight in ny individul ptient ws less thn 5% of initil body weight. Written informed onsent ws obtined from eh ptient before entering these studies, whih were pproved by the lol hospitl ethil ommittee. EXPERIMENTL DESIGN ll 1 ptients reeived regimen whih onsisted of low holesterol diet (1 mg/dy) s desribed previously8 plus bedtime heni id given in three different doses (25, 5, nd 75 mg dily) for one month eh in rndom order; nd regimen B, whih onsisted of norml holesterol diet8 (6 mg/dy) plus bedtime heni id in the sme doses s for regimen. Five of the 1 ptients were rndomly lloted to strt on regimen, nd the other five to strt on regimen B. t the end of three months, ptients finishing regimen rossed over to regimen B nd vie vers, so tht t six months ll 1 ptients hd been studied on both regimens. t this stge six ptients (three from eh group) were studied on regimen C (the onventionl regimen, whih onsisted of norml holesterol diet with heni id given in three divided doses t meltimes). On this regimen, heni id ws given in doses of 375, 75, nd 1125 mg dily. On ll three tretment regimens, ll three different doses of heni id were given for one month eh in rndom order. t the end of eh month, fsting gllbldder bile ws obtined by nsoduodenl intubtion nd intrvenous infusion of holeystokinin (Boots Ltd) dissolved in norml sline. t eh monthly visit, dily bowel frequeny during the previous week ws reorded. t eh monthly visit, the ptients were lso seen by professionl dietiin. t the first visit, the ptients were given smple menu, lredy published.8 For the holesterol-ontining items 281 (met, eggs, nd milk) list of lterntive items ontining the sme mount of holesterol ws lso given to the ptients to ensure vriety. t subsequent visits, the dietiin questioned the ptients bout ompline, nd disussed problems or queries tht hd risen. Ptients were lso enourged to telephone the dietiin to disuss problems s soon s they rose between visits. Bile smpling during heni id tretment ws not strted until the dietiin ws stisfied tht the ptient hd stuk refully to the diet for t lest one month. Sttistil omprisons between different tretment regimens were bsed on the pired t test, nd nlysis of ovrine. BILE NLYSIS ll bile smples from eh ptient were nlysed in one bth t the end of the experiment. Totl bile id onentrtion ws mesured by 3-hydroxysteroid dehydrogense enzyme ssy.1 11 Phospholipids were mesured by the method of Brtlett,12 nd holesterol ws mesured by the holesterol oxidse method13 in n liquot of bile diluted t the bedside in isopropnol. Cholesterol sturtion index ws lulted using the polynomil eqution developed by Thoms nd Hofmnn,'4 bsed on the limits of holesterol solubility desribed by Hegrdt nd Dm15 nd Holzbh et l. 16 Results STURTION INDEX OF FSTING GLLBLDDER BILE On ll three tretment regimens there ws signifint orreltion between sturtion index nd dose of heni id (mg/kg/dy). If the pretretment sturtion index is tken into ount (Figs. 1 nd 2), for regimen (bedtime heni id plus low holesterol diet) r=-*45, P<-1; for regimen B (bedtime heni id plus norml holesterol diet) r=-*52, P<-1; for regimen C (meltime heni id plus norml holesterol diet) r=-.68, P<.1. Minimum effetive dose on the onventionl regimen (C) ws 14. mg/kg/dy (Fig. 1). On bedtime heni id (regimen B) it ws 12-4 mg/kg/dy, nd on bedtime heni id plus low holesterol diet (regimen ) it fell to 8.4 mg/kg/dy (Fig. 2). There ws signifint differene in interept between the two regression lines (P<.1). If the pretretment sturtion index is exluded, there still remins signifint orreltion between the sturtion index nd dose of heni id on regimens nd C (on regimen, r=-.45, P<-2; on regimen C, r=-*47, P<.5). Minimum effetive dose lulted from these regression lines ws 8-3 nd 14. mg/kg/dy on regimens nd C respetively. Gut: first published s /gut on 1 pril Downloded from on 2 ugust 218 by guest. Proteted by opyright.

3 I -x 1. W -,o U 4-2 *~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~ t l 1 o Cheni id dose (mg/kg/dy) Fig. 1 Doselresponse reltionship on onventionl regimen (regimen C: meltime heni idplus norml hol'esterol diet). Norml holesterol diet. * Pre-tretment. n=24. r=--68, P<-1. 2.; ID I 1Ln_ C *8-2,.2.6- ~2.4- * _ * o ~~....Q'I i oo l l!! ' g Cheni id doselr(mg/kg/dy) Fig. 2 Doselresponse reltionship on regimen (bedtime heni id plus low holesterol diet) nd regimen B (bedtime heni id plus norml holesterol diet). * Pre-tretment. Norml holesterol dietr= --52, P<-1. Low holesterol dietr=--45, P<-1. In Fig. 3, sturtion index for individul subjets hs been plotted for the three doses studied (25, 5, nd 75 mg dily) on regimen nd regimen B. t dose of 75 mg dily on regimen llo1 ptients hd sturtion index of less thn 1 nd seven of the * *4- Sturtion index (H nd D) 1 2 1** Mudgl, Kupfer, nd Northfield o Cheni id (mg/dy) Fig. 3 Doselresponse reltionship in individul subjets on regimen (bedtime heni idplus low holesterol diet: ) nd on regimen B (bedtime heni idplus norml holesterol diet: ). ptients hd sturtion index of less thn X8. t the sme dose, on regimen B, only seven of the 1 ptients hd sturtion index of less thn 1 nd only three sturtion index of less thn.8. On regimen nd regimen B respetively, sturtion index (men±sem) ws -94±-5 nd 1-2±-6 on 25 mg dily (P<-1),.83±-4 nd -92±-6 on 5 mg ily (P<-5), nd -71±-4 nd -86±-6 on 75 mg dily (P<.1). BOWEL FREQUENCY Pretretment bowel frequeny (men±sem) ws -8±-1 motions dily. On meltime heni id (regimen C) it ws -9±-1 on 375 mg dily nd 1-1±-1 on 75 mg dily, but rose to 1-8±-3 on 1125 mg dily (P<-2). The highest dose for bedtime heni id plus low holesterol diet (regimen ) ws 75 mg dily, nd this gve the sme bowel frequeny (1.1±.1) s meltime heni id. Disussion In defining our minimum effetive dose for group of gllstone ptients s the dose giving men sturtion index of -8 we hve used the sme riteri ~ Gut: first published s /gut on 1 pril Downloded from on 2 ugust 218 by guest. Proteted by opyright.

4 Minimum effetive dose ofheni idforgllstoneptients 283 s those given for reommended dose by Dowling nd ollegues.5 They bsed this reommendtion on the finding tht men sturtion index of -8 ws ssoited with onsistent gllstone dissolution5 nd ws hieved using men dose of 14.4 mg/kg/dy. They rried out dose response study9 for heni id, nd men sturtion index of -8 ws gin hieved with n verge dose of mg/kg/dy. Like them we inluded pretretment sturtion index. If this is exluded, signifint dose response reltionship is still found for our dt, nd the vlues for minimum effetive dose re virtully unhnged. Our experimentl design ws of neessity omplited one, beuse we wished to study three different tretment regimens, three different doses of heni id being given for one month eh on ll three regimens. We relised tht not ll ptients would omplete the full nine months' study, whih involved totl of 1 intubtions. Our first priority ws to determine minimum effetive dose on bedtime heni id tken both with nd without low holesterol diet. ll 1 ptients prtiipted in these two regimens in rndom order. Minimum effetive dose ws 12.4 mg/kg/dy with bedtime dministrtion of heni id nd norml holesterol diet (Fig. 2). The ddition of low holesterol diet to bedtime heni id dministrtion enhned the effet of heni id t ll doses studied, nd signifintly ltered the regression line defining the dose response reltionship. It further redued minimum effetive dose to 8.4 mg/kg/dy. On this dose, only one ptient hd super-sturted bile (sturtion index 1.3). Our seond priority ws to onfirm tht our results on the onventionl regimen of meltime heni id nd norml holesterol diet were similr to those of other groups. Six of the 1 ptients who hd lredy prtiipted in the other two dose response studies greed to tke prt in this third dose response study. These six ptients did not differ from the others in terms of weight, perentge idel body weight, nd ge (Tble). There were three men nd three women, ompred with four men nd six women. s ll doses of heni id were given for one month, n order effet would not hve been expeted but, if present, it would hve tended to minimise ny differene between this nd the other two regimens. The minimum effetive dose obtined, 14- mg/kg/dy, ws very similr to the vlue of 14-4 mg/kg/dy reported by Iser et l. to give men sturtion index of -85 The low holesterol diet proved muh more eptble to the ptients thn low lorie diet nd mny of the ptients ontinued on it for preferene fter the studies hd been ompleted. The min priniples of the diet were to use mrgrine insted of butter, to et only len met with the ft removed, to drink only skimmed milk, nd to void eggs ompletely. Inresed bowel frequeny is troublesome side-effet of heni id. It n be voided if low enough dose is given, s this effet is well known to be dose-relted. ' 3 4' In the urrent study, dily bowel frequeny remined unhnged on 375 nd 75 mg heni id dily (5.5 nd 11 mg/kg/dy), but inresed signifintly on 1125 mg dily (16.5 mg/kg/dy). s reported in previous study,7 single bedtime dose of heni id did not inrese bowel frequeny when ompred with meltime dministrtion of the sme totl dily dose of heni id. Thus, dministrtion of heni id t bedtime with low holesterol diet enbles the minimum effetive dose for gllstone dissolution to be pproximtely hlved, thus preventing dirrhoe nd reduing the ost of tretment. We re grteful to Weddel Phrmeutils for finnil support, Mrs Moy Gnnon for nursing ssistne, nd Mr R Bird for tehnil ssistne. Referenes 1 Dnzinger RG, Hofmnn F, Shoenfield LJ et l. Dissolution of holesterol gllstones by henodeoxyholi id. N Engl J Med 1972; 286: Bell GD, Whitney B, Dowling RH. Gllstone dissolution in mn using henodeoxyholi id. Lnet 1972; 11: Thistle JL, Hofmnn F. Effiy nd speifiity of henodeoxyholi id therpy for dissolving gllstones. N Engl J Med 1973; 289: Jmes, Cullen J, Bouhier ID. Chenodeoxyholi id therpy for gllstones. Effetiveness, toxiity nd influene on bile id metbolism. Q J Med 1975; 44: Iser JH, Dowling RH, Mok HYI et l. Chenodeoxyholi id tretment of gllstones- follow-up report nd nlysis of ftors influening response to therpy. N Engl J Med 1975; 293: Mton PM, Murphy GM, Dowling RH. Ursodeoxyholi id tretment of gllstones. Dose response study nd possible mehnism of tion. Lnet 1977; 2: Mudgl DP, Bird R, Northfield TC. Optiml timing of doses of heni id in ptients with gllstones. Br MedJ 1979; 1: Mudgl DP, Bird R, Blkwood WS et l. Low holesterol diet: Enhnement of effet of CDC in ptients with gllstones. Br Med J 1978; 2: Mok HYI, Bell GD, Dowling RH. Effet of different doses of henodeoxyholi id on bile lipid omposition nd on side effets in ptients with gllstones. Lnet 1974; 11: Tlly P. Enzymti nlysis of steroid hormones. In: Glik D, ed. Methods of biohemil nlysis. New York: Intersiene, 196: 8:119. Gut: first published s /gut on 1 pril Downloded from on 2 ugust 218 by guest. Proteted by opyright.

5 284 Mudgl, Kupfer, nd Northfield 11 dmirnd WH, Smll DM. The physiohemil bsis of holesterol gllstone formtion in mn. J Clin Invest 1968; 47: Brtlett GR. Phosphorus ssy in olumn - hromtogrphy. J Biol Chem 1959; 234: Rod, Festi D, Sm C et l. Enzymti determintion of holesterol in bile. Clin Chim t 1975; 64: Thoms PJ, Hofmnn F. simple lultion of lithogeni index of bile. Experimentl biliry lipid omposition on retngulr oordintes. Gstroenterology 1973; 65: Hegrdt FS, Dm H. The solubility of holesterol in queous solution of bile slts nd leithin. Z Ernehrungswiss 1971; 1: Holzbh RT, Mrsh M, Olszewski M et l. Cholesterol solubility in bile: evidene tht supersturted bile is frequent in helthy mn. J Clin Invest 1973; 52: Gut: first published s /gut on 1 pril Downloded from on 2 ugust 218 by guest. Proteted by opyright.